Salinomycin as a potential chemotherapeutic compound in cisplatin-resistant ovarian cancer : effects and mechanisms

Abstract

Ovarian cancer is the most frequent cause of death from gynecological cancer. Even though there are a lot of options in treating gynecological malignancies, the therapeutic effect of ovarian cancer nowadays is still unfavourable, especially in treatment of the patients diagnosed with late stage disease. The development of chemotherapeutic drug resistance during the treatment of ovarian cancer is thought to cause treatment failure and the high mortality rate. Thus, searching for alternative agents to overcome chemoresistance during the treatment of ovarian cancer is essential. Salinomycin, a polyether ionophore antibiotic that has recently been shown not only to kill human breast cancer stem cell-like cells, but also to induce apoptosis and overcome multiple mechanisms of resistance to apoptosis in human cancer cells. These results strongly suggested that salinomycin should be regarded as an anticancer compound. This study aims at exploring the anticancer effects and mechanism of salinomycin on cisplatin-resistant human ovarian cancer cell line in vitro and in vivo. Concentration (0.01-200µM)- and time (24-72 h)- dependent growth inhibitory effects of salinomycin were observed in 6 ovarian cancer cell lines (OV2008, C13, A2780, A2780-cp, SKOV3 and OVCAR3) by measuring cell viability using the resazurin reduction assay. IC50 (24 h) range of salinomycin on these 6 cell lines was 1.7-7.4 µM. After cisplatin-resistant C13 cells were treated with salinomycin, the percentages of apoptotic cells determined by flow cytometry were significantly increased, showing a concentration- and time-dependent manner. But no cell cycle arrest in the G1/G0, S and G2/M phases was detected between salinomycin-treated cells and control cells. Bio-Plex phosphoprotein 5-plex assay (Akt, IκB-α, ERK1/2, JNK and p38 MAPK) revealed a marked time- and concentration-dependent increase in the phosphorylation of p38 MAPK following salinomycin treatment. Pretreatment with SB202190, an inhibitor of p38 MAPK, markedly inhibited salinomycin-induced apoptosis. Moreover, salinomycin significantly suppressed the growth of tumors in tumor (C13) xenograft model. The tumor cell apoptosis in situ analyzed by immunohistochemistry staining of cleaved caspase-3 indicated that more apoptotic cells were observed in tumor treated with salinomycin than control tumor. The results of this research demonstrated that salinomycin is a potent compound against cisplatin-resistant human ovarian cancer cell line C13 in vitro and indicates significant in vivo efficacy in tumor (C13) xenograft model. Salinomycin can inhibit the growth of cisplatin-resistant human ovarian cancer cell line C13 efficiently through induction of apoptosis, which might be associated with activation of p38 MAPK. Salinomycin shows substantial promise for further development as a potential agent for treating drug-resistant ovarian cancer.